Development of anti-human CADM1 monoclonal antibodies as a potential therapy for adult T-cell leukemia/lymphoma
Development of anti-human CADM1 monoclonal antibodies as a potential therapy for adult T-cell leukemia/lymphoma
复制标题
DOI：
10.1007/s12185-020-02939-1
复制
发表时间：
2020-07-12
影响因子：
2.1
通讯作者：
Morishita, Kazuhiro
中科院分区：
文献类型：
--
作者：
Chilmi, Syahrul;Nakahata, Shingo;Morishita, Kazuhiro
成人T细胞白血病/淋巴瘤（ATLL）是一种高度侵袭性和难治性的T细胞恶性肿瘤，预后差。我们以前确定，细胞粘附分子1（CADM 1）在ATLL细胞中持续过表达，并且CADM 1表达增加了ATLL细胞对内皮细胞的粘附能力，并促进了异种移植小鼠模型中ATLL细胞的器官侵袭。在这项研究中，我们首先表明，新开发的几种抗人CADM 1抗体，这是完全的人IgG抗体产生的噬菌体展示方法，特异性识别ATLL细胞上的CADM 1。尽管大多数CADM 1抗体对CADM 1阳性ATLL细胞没有直接的细胞毒性作用，但克隆089-084表现出弱但显著的抗体依赖性细胞介导的细胞毒性活性。此外，克隆103-189有效地抑制内皮细胞和CADM 1阳性ATLL细胞之间的相互作用。此外，在脾内移植表达CADM 1的EL 4小鼠淋巴瘤细胞的小鼠中，103-189的治疗显著抑制了CADM 1阳性EL 4细胞的器官侵袭，导致小鼠存活时间的改善。因此，由于抗CADM 1抗体可用于抑制ATLL患者的器官侵袭，因此抗CADM 1抗体与化疗药物的组合使用可有益于ATLL细胞的有效消除。
Adult T-cell leukemia/lymphoma (ATLL) is a highly invasive and refractory T-cell malignancy, with poor prognosis. We previously identified that cell adhesion molecule 1 (CADM1) is overexpressed consistently in ATLL cells, and that CADM1 expression increases the adhesion capacity of ATLL cells to endothelial cells and promotes the organ invasion of ATLL cells in a xenograft mouse model. In this study, we first show that newly developed several anti-human CADM1 antibodies, which were complete human IgG antibodies generated by phage display method, specifically recognize CADM1 on ATLL cells. Although most of the CADM1 antibodies did not have a direct cytotoxic effect against CADM1-positive ATLL cells, clone 089-084 exhibited weak but significant antibody-dependent cell-mediated cytotoxic activity. Moreover, clone 103-189 effectively inhibits the interaction between endothelial cells and CADM1-positive ATLL cells. Furthermore, in mice bearing intra-splenic transplantation of EL4 mouse lymphoma cells expressing CADM1, the treatment of 103-189 significantly suppressed the organ invasion of CADM1-positive EL4 cells, resulting in improved survival time of mice. Therefore, since the anti-CADM1 antibody may be useful for the suppression of organ invasion in ATLL patients, combination use of the anti-CADM1 antibody with chemotherapy drugs could be beneficial for the efficient elimination of ATLL cells.